1. Field of the Invention
This invention relates to a process for the preparation of five-membered or six-membered ring lactams from aliphatic .alpha.,.omega.-dinitriles by a combination of biological and chemical techniques. More particularly, an aliphatic .alpha.,.omega.-dinitrile is first converted to an ammonium salt of an .omega.-nitrilecarboxylic acid in aqueous solution using a catalyst having an aliphatic nitrilase (EC 3.5.5.7) activity, or a combination of nitrile hydratase (EC 4.2.1.84) and amidase (EC 3.5.1.4) activities. The ammonium salt of the .omega.-nitrilecarboxylic acid is then converted directly to the corresponding lactam by hydrogenation in aqueous solution, without isolation of the intermediate .omega.-nitrilecarboxylic acid or .omega.-aminocarboxylic acid. When the aliphatic .alpha.,.omega.-dinitrile is also unsymmetrically substituted at the .alpha.-carbon atom, the nitrilase produces the .omega.-nitrilecarboxylic acid ammonium salt resulting from hydrolysis of the .omega.-nitrile group with greater than 98% regioselectivity, thereby producing only one of the two possible lactam products during the subsequent hydrogenation.
2. Description of the Related Art
Nitriles are readily converted to the corresponding carboxylic acids by a variety of chemical processes, but these processes typically require strongly acidic or basic reaction conditions and high reaction temperatures, and usually produce unwanted byproducts and/or large amounts of inorganic salts as unwanted byproducts. Processes in which enzyme-catalyzed hydrolysis convert nitrile substrates to the corresponding carboxylic acids are often preferred to chemical methods, since these processes are often run at ambient temperature, do not require the use of strongly acidic or basic reaction conditions, and do not produce large amounts of unwanted byproducts. An additional advantage of the enzyme-catalyzed hydrolysis of nitriles over chemical hydrolysis is that, for the hydrolysis of a variety of aliphatic or aromatic dinitriles, the enzyme-catalyzed reaction can be highly regioselective, where only one of the two nitrile groups is hydrolyzed to the corresponding carboxylic acid ammonium salt.
A nitrilase enzyme directly converts a nitrile to the corresponding carboxylic acid ammonium salt in aqueous solution without the intermediate formation of an amide. The use of aromatic nitrilases for the hydrolysis of aromatic nitriles to the corresponding carboxylic acid ammonium salts has been known for many years, but it is only recently that the use of aliphatic nitrilases have been reported. Kobayashi et al. (Tetrahedron, (1990) vol. 46, 5587-5590; J. Bacteriology, (1990), vol. 172, 4807-4815) have described an aliphatic nitrilase isolated from Rhodococcus rhodochrous K22 which catalyzed the hydrolysis of aliphatic nitriles to the corresponding carboxylic acid ammonium salts; several aliphatic .alpha.,.omega.-dinitriles were also hydrolyzed, and glutaronitrile was converted to 4-cyanobutyric acid ammonium salt with 100% molar conversion using resting cells as catalyst. A nitrilase from Comamonas testosteroni has been isolated which can convert a range of aliphatic .alpha.,.omega.-dinitriles to either the corresponding .omega.-nitrilecarboxylic acid ammonium salt or the dicarboxylic acid diammonium salt (Canadian patent application CA 2,103,616 (1994/02/11); S. Levy-Schil, et al., Gene, (1995), vol. 161, 15-20); for the hydrolysis of adiponitrile, a maximum yield of 5-cyanovaleric acid ammonium salt of ca. 88% was obtained prior to complete conversion of the 5-cyanovaleric acid ammonium salt to adipic acid diammonium salt.
M. L. Gradley and C. J. Knowles (Biotechnology Lett., (1994), vol. 16, 41-46) have reported the use of suspensions of Rhodococcus rhodochrous NCIMB 11216 having an aliphatic nitrilase activity for the hydrolysis of several 2-methylalkylnitriles. Complete conversion of (+/-)-2-methylbutyronitrile to 2-methylbutyric acid ammonium salt was obtained, while the hydrolysis of (+/-)-2-methylhexanenitrile appeared to be enantiospecific for the (+)-enantiomer. C. Bengis-Garber and A. L. Gutman (Appl. Microbiol. Biotechnol., (1989), vol. 32, 11-16) have used Rhodococcus rhodochrous NCIMB 11216 as catalyst for the hydrolysis of several dinitriles. In this work, fumaronitrile and succinonitrile were converted to the corresponding .omega.-nitrilecarboxylic acid ammonium salts, while glutaronitrile, adiponitrile, and pimelonitrile were converted to the corresponding dicarboxylic acid diammonium salts.
A combination of two enzymes, nitrile hydratase (NHase) and amidase, can be also be used to convert aliphatic nitriles to the corresponding carboxylic acid ammonium salts in aqueous solution. Here the aliphatic nitrile is initially converted to an amide by the nitrile hydratase and then the amide is subsequently converted by the amidase to the corresponding carboxylic acid ammonium salt. A wide variety of bacterial genera are known to possess a diverse spectrum of nitrile hydratase and amidase activities, including Rhodococcus, Pseudomonas, Alcaligenes, Arthrobacter, Bacillus, Bacteridium, Brevibacterium, Corynebacterium, and Micrococcus. Both aqueous suspensions of these microorganisms and the isolated enzymes have been used to convert nitriles to amides and carboxylic acid ammonium salts.
P. Honicke-Schmidt and M. P. Schneider (J. Chem. Soc., Chem. Commun., (1990), 648-650) have used immobilized Rhodococcus sp. strain CH 5 to convert nitriles and dinitriles to carboxylic acid ammonium salts and .omega.-nitrilecarboxylic acid ammonium salts, respectively. The cells contain both a nitrile hydratase and amidase activity which converts glutaronitrile to 4-cyanobutyric acid ammonium salt in 79% isolated yield based on 92% conversion of substrate. A. J. Blakely et al. (FEMS Microbiology Lett., (1995), vol. 129, 57-62) have used the nitrite hydratase and amidase activity of suspensions of Rhodococcus AJ270 to regiospecifically hydrolyze malononitrile and adiponitrile to produce only the corresponding .omega.-nitrilecarboxylic acid ammonium salts. H. Yamada et al. (J. Ferment. Technol., (1980), vol. 58, 495-500) describe the hydrolysis of glutaronitrile to a mixture of 4-cyanobutyramide, 4-cyanobutyric acid, glutaric acid and ammonia using Pseudomonas sp. K9, which contains both a nitrite hydratase and amidase. K. Yamamoto et al. (J. Ferment. Bioengineering, 1992, vol. 73, 125-129) described the use of Corynebacterium sp. CH 5 cells containing both a nitrite hydratase and amidase activity to convert trans-1,4-dicyanocyclohexane to trans-4-cyanocyclohexanecarboxylic acid ammonium salt in 99.4% yield.
J. L. Moreau et al. (Biocatalysis, (1994), vol 10. 325-340) describe the hydrolysis of adiponitrile to adipic acid, adipamide, and adipamic acid through the intermediate formation of 5-cyanovaleric acid using Brevibacterium sp. R312 (nitrite hydratase and amidase activity). A. Kerridge et al. (Biorg. Medicinal Chem., (1994), vol. 2, 447-455) report the use of Brevibacterium sp. R312 (nitrite hydratase and amidase activity) to hydrolyze prochiral 3-hydroxyglutaronitrile derivatives to the corresponding (S)-cyanoacid ammonium salts. European Patent 178,106 B 1 (Mar. 31, 1993) discloses selective transformation of one of the cyano groups of an aliphatic dinitrile to the corresponding carboxylic acid, amide, ester or thioester using the mononitrilase activity (defined as either nitrilase or a combination of nitrite hydratase/amidase) derived from Bacillus, Bacteridium, Micrococcus or Brevibacterium. In addition to the many examples of bacterial catalysts having nitrilase activity or nitrite hydratase/amidase activity, Y. Asano et al. (Agric. Biol. Chem., (1980), vol. 44, 2497-2498) demonstrated that the fungus Fusarium merismoides TG-1 hydrolyzed glutaronitrile to 4-cyanobutyric acid ammonium salt, and 2-methylglutaronitrile to 4-cyanopentanoic acid ammonium salt.
No prior art has been found which describes the hydrogenation of ammonium salts of aliphatic .omega.-nitrilecarboxylic acids in aqueous solution to directly produce the corresponding lactams. In closely related art, U.S. Pat. No. 4,329,498 describes the hydrogenation of muconic acid mononitrile to 6-aminocaproic acid (6-ACA) in dry ethanol saturated with ammonia, using a Raney nickel catalyst #2. After removal of the hydrogenation catalyst, heating the ethanolic solution of 6-ACA to 170.degree. C.-200.degree. C. was expected to result in the cyclization of 6-ACA to caprolactam. The reductive cyclization of either .beta.-quinoxalinylpropanoic acids (E. C. Taylor et al., J. Am. Chem. Soc., (1965), vol. 87, 1984-1990), or the related 2-(2-carboxyethyl)-3(4H)-quinoxalone (E. C. Taylor et al., J. Am. Chem. Soc., (1965), vol. 87, 1990-1995) by hydrogenation in 1 N sodium hydroxide solution using Raney nickel as the catalyst has been reported to produce the corresponding five-membered ring lactams, but only after removal of the catalyst from the product mixture and acidification of the resulting filtrate. The authors state that for any of these reductions, "lactam formation can only proceed in acidic solution" (page 1992, second paragraph), presumably requiring the presence of the protonated carboxylic acid and not the carboxylate salt. U.S. Pat. No. 4,730,040 discloses a process for the preparation of caprolactam, reacting an aqueous solution of 5-formylvaleric acid with ammonia and hydrogen in the presence of a hydrogenation catalyst, following which ammonia is separated from the product mixture and the resulting solution of 6-ACA is heated to 300.degree. C.
Previous work has disclosed single cells containing both nitrile hydratase and amidase activities that have been used to convert nitriles and dinitriles to various acid ammonium salts. However, no prior art has been found which describes the cyclization of ammonium salts of aliphatic .omega.-aminocarboxylic acids under the hydrogenation reaction conditions of the present invention (i.e., in an aqueous solution containing an excess of added ammonium hydroxide) to produce the corresponding lactams. In closely related art, the cyclization of aliphatic .omega.-aminocarboxylic acids (but not the ammonium salts) to the corresponding lactams under a variety of reaction conditions has been reported. F. Mares and D. Sheehan (Ind. Eng. Chem. Process Des. Dev., (1978), vol. 17, 9-16) have described the cyclization of 6-aminocaproic acid (6-ACA) to caprolactam using water or ethanol as solvent. In water, the cyclization reaction was reversible at concentrations below 1 mol/kg (ca. 1 M), and the concentration of caprolactam increased with increasing temperature; at a total concentration of 6-ACA and caprolactam of 0.85 mol/kg (ca. 0.85 M), the percentage of caprolactam was reported to increase from 38.7% at 180.degree. C. to 92.2% at 250.degree. C. In ethanol, a 98% yield of caprolactam was obtained at 200.degree. C., reportedly due to a shift in the equilibrium which favors the free-acid/free-amine form of 6-ACA in ethanol, rather than the intramolecular alkylammonium carboxylate form of 6-ACA which predominates in water. A process for the production of caprolactam from 6-ACA is also described in U.S. Pat. No. 4,599,199, where 6-ACA is introduced into a fluidized alumina bed in the presence of steam at from 290.degree. C. to 400.degree. C. The synthesis of five-, six- and seven-membered ring lactams by cyclodehydration of aliphatic .omega.-aminoacids on alumina or silica gel in toluene, and with continuous removal of the water produced during the reaction, has been reported by A. Blade-Font (Tetrahedron Letters, (1980), vol. 21, 2443-2446). A free amino group (unprotonated) was reported to be necessary for cyclodehydration to take place.
No prior art has been found which describes the hydrogenation of ammonium salts of aliphatic .omega.-nitrilecarboxylic acids in aqueous solution containing methylamine to directly produce the corresponding N-methyl lactams. In closely related art, 1,5-dimethyl-2-pyrrolidinone was prepared by the hydrogenation of an aqueous solution of levulinic acid and methylamine in water using a Raney nickel catalyst at 140.degree. C. and 1000-2000 psig of hydrogen R. L. Frank et al., Org. Sytheses, (1954), Coll. Vol. 3, 328-329). The resulting 4-N-methylaminopentanoic acid methylammonium salt was then cyclized to the corresponding lactam by filtration of the product mixture and distillation of the filtrate to remove water and methylamine. N-alkyl lactams have also been produced by the direct hydrogenation of an aqueous mixture containing 2-methylglutaronitrile, a primary alkylamine, and a hydrogenation catalyst, the process yielding a mixture of 1,3- and 1,5-dialkylpiperidone-2 (U.S. Pat. No. 5,449,780). N-Substituted 2-pyrrolidinones have been prepared by the reaction of .gamma.-valerolactone with an alkyl amine at 110-130.degree. C., then heating the resulting mixture to 250-270.degree. C. while distilling off water (F. B. Zienty and G. W. Steahly, J. Am. Chem. Soc., (1947), vol. 69, 715-716).
The above processes for the production of lactams or N-alkyllactams suffer from one or more of the following disadvantages: the use of temperatures in excess of 250.degree. C. to obtain high yields of lactams when using water as a solvent, the removal of water from the reaction mixture to drive the equilibrium toward lactam formation, the adjustment of the pH of the reaction mixture to an acidic value to favor lactam formation, or the use of an organic solvent in which the starting material is sparingly soluble. Many of these processes generate undesirable waste streams, or mixtures of products which are not easily separated. A significant advance would be a process for the conversion of an aliphatic .alpha.,.omega.-dinitrile to the corresponding lactam or N-methyllactam in aqueous solution, in high yield with high regioselectivity, with little byproduct or waste stream production, and with a facile method of product recovery.